A highly sensitive and reproducible system of antigen-induced, antigen-specific activation of human B cells was developed which led to a precise delineation of the dichotomy and overlap between antigen-specificity and polyclonality of in vitro B cell responses. The profile and kinetics of the circulating human antigen-specific B cell repertoire were described in this system and the heterogeneous mechanisms of modulation of B cell responses were precisely delineated. The system was T cell dependent and modulated by multiple interacting subsets of helper and suppressor T cells. B cells were also shown to be directly tolerized by high antigen concentrations. Monocytes were absolutely required for the system; they were suppressive in excess numbers; they presented antigen to the T cells in the T cell-monocyte-B cell interactions and this required strict HLA-DR compatibility between the T cell and monocyte. On the other hand, the B cell required direct interaction with the antigen and could not be triggered by antigen presented via the monocyte. The complex mechanisms and multiple sites of action of corticosteroids and cytotoxic agents on the activation and immunoregulation of human lymphocyte function were delineated, as were the abnormalities of immune function in various disease states.